# BLRD Research Career Scientist Award Application

> **NIH VA IK6** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

The overarching goal of my research program is to understand tissue specific immunity with focus on the lungs.
Immune cells continuously surveil the lungs to respond quickly to infections. Mycobacterium tuberculosis (Mtb)
causes chronic tuberculosis (TB) and Francisella tularensis causes acute tularemia—two bacteria that cause
respiratory infectious diseases. I have developed two large-scale T cell epitope discovery programs that leverage
our strengths and my forte: the Merit supports the Mtb program; and AI137982 “Molecular Basis of CD1D and
Natural Killer T Cell Function”, awarded in August 2019, after the RCS began, supports F. tularensis research.
New support has been sought via a response to an RFA BAA-NIAID-DAIT-75N93022R00023: “FUNCTIONAL
IMMUNOPEPTIDOMICS: Large-Scale F tularensis-derived Epitope Discovery & Correlates of T Cell Immunity”.
 Our Mtb work addresses a critical unmet need for an effective vaccine against TB that will significantly
improve the quality of life of our Veterans. Mtb lives and multiplies within the host immune cell called
macrophages, which are voracious eaters of bacteria and other foreign substances. Mtb has evolved ways to
prevent macrophages from doing so, making life within infected cells possible. To get rid of the infection, the
host needs to engage the killer cells of the immune system, one such killer cell is called CD8+ T cell. CD8+ T
cells are equipped to find infected cells in very specific manner when antigens are presented in association with
the hosts’ Human Leukocyte Antigen (HLA)-I molecule. HLA-I are different between individuals making T cell
vaccine development difficult. Fortunately, HLA-I can be grouped into nine supertypes—B7 is one such
supertype expressed by 40—45% of the human population. Once specific antigen recognition occurs, these
effector cells deploy killing mechanisms to destroy the infected cells, leaving no place for the bacteria to live.
 Hence, the overarching goal of the Merit research is to develop a vaccine platform against TB that harnesses
CD8+ T cell functions. This program leverages 30+ years of my experience in the field of antigen processing and
presentation to T cells. Thus, in a systematic approach to vaccine design, our work involves pre-clinical studies
that aims to identify MTb-derived antigens expressed only by infected macrophages so that CD8+ T cells can
recognize such antigens, kill infected cells, and, thereby, confer protection to the host. In addition to vaccine
design, our research will develop platforms for the delivery of next generation TB vaccines directly to the site of
Mtb infection which is the lungs. We have made great strides toward both these goals: To facilitate the antigen
discovery goal, we have developed new HLA-I transgenic humanized mouse lines. Then in a high-throughput
antigen presentation assay that leverages a novel ultrahigh-density peptide arrays, we discovered 100s of
peptide antigens that are presented by four common human MHC mole...

## Key facts

- **NIH application ID:** 10921693
- **Project number:** 2IK6BX004595-06
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** SEBASTIAN JOYCE
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2019-04-01 → 2031-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10921693

## Citation

> US National Institutes of Health, RePORTER application 10921693, BLRD Research Career Scientist Award Application (2IK6BX004595-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10921693. Licensed CC0.

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